Is DSP p.Ala1584Thr (c.4750G>A) pathogenic?

DSP p.Ala1584Thr (c.4750G>A) is classified Likely benign in DSP (ClinVar, Multiple submitters, 8 submitters; last evaluated 2025-12-18). AlphaMissense: likely benign (0.0866); Rare (popmax 0.154%, eas); Associated with Cardiovascular phenotype.

What condition is associated with DSP p.Ala1584Thr (c.4750G>A)?

DSP p.Ala1584Thr (c.4750G>A) is associated with Cardiovascular phenotype, cardiomyopathy, arrhythmogenic cardiomyopathy with wooly hair and keratoderma (ClinVar).

How common is DSP p.Ala1584Thr (c.4750G>A) in the general population?

DSP p.Ala1584Thr (c.4750G>A) is rare (popmax 0.154%, eas) (gnomAD).

What do computational predictors say about DSP p.Ala1584Thr (c.4750G>A)?

AlphaMissense predicts likely benign (score 0.0866) — an in-silico prediction, not a clinical call.

DSP p.Ala1584Thr

c.4750G>A · rs191778417 · VCV44921

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

AlphaMissense

likely benign

0.0866 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.154%, eas)

Missense predictors

0/2 damaging

AlphaMissense, REVEL

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.0866	likely benign
REVEL	0.085	moderately benign-leaning
⇒ AlphaMissense and REVEL both call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.8	GERP 1.9, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 12 kb · p 0.0024 · regional, not allelic
Overall
CADD	18.72	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.154% East Asian · 69/44,880 alleles

Filtering AF 0.125% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.114%

Overall 0.00638% 103/1,614,078 alleles · rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.154%	650
Remaining individualsnot grpmax-eligible	0.0048%	20,835
European (non-Finnish)	0.00237%	42,143
South Asian	0.0022%	45,539
African / African-American	0.00133%	75,030

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: DSP
Protein: p.Ala1584Thr
Coding: c.4750G>A
MANE Select: NM_004415
dbSNP: rs191778417
Type: single nucleotide variant
Location: chr6:7580940 (GRCh38)
Gene constraint: LOEUF 0.443 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 1584: a UniProt-annotated variant site (in arvd8; uncertain significance); a UniProt-annotated variant site (in dcwhkta; uncertain significance); a UniProt-annotated variant site (in dcwhk; uncertain significance; abolishes expression in the myocardium); the 'central fibrous rod domain' region; the 'binds to telomeres' region; a UniProt-annotated variant site (in arvd8; likely pathogenic; results in an unstable protein that forms perinuclear aggregates); a UniProt-annotated variant site (in arvd8 and dcwhkta; uncertain significance); a UniProt-annotated variant site (in arvd8)

Full DSP gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Cardiovascular phenotype — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: cardiomyopathy arrhythmogenic cardiomyopathy with wooly hair and keratoderma arrhythmogenic right ventricular dysplasia 8

Similar variants

DSP p.Ala1584Val Uncertain significance ★★ ⚠ same residue
DSP p.Ala1584= Likely benign ★★ same residue
DSP p.Ala1584Gly Uncertain significance ★ ⚠ same residue
DSP p.Ala1584Pro Uncertain significance ★ ⚠ same residue
DSP p.Ala1584Ser Conflicting classifications of pathogenicity ★ ⚠ same residue
DSP p.Ala1584fs Pathogenic ★ same residue
DSP c.1141-2A>T Likely pathogenic ★★ same condition
DSP c.1266+2T>C Likely pathogenic ★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/dsp-p-ala1584thr (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown